Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

BACKGROUND Canine leishmaniosis is caused by the protozoan parasite Leishmania infantum that is transmitted by a phlebotomine sand-fly vector. Visceral leishmaniosis is a zoonotic disease, for which dogs are considered the chief reservoir for transmission to humans. Leishmaniosis is an emerging disease in the UK and there is a risk that it might become epidemic and endemic, should future climate conditions support the life-cycle of a suitable vector. The course of L. infantum infection in dogs is determined by a complex interaction between host and pathogen. Both innate and adaptive immune systems engage with the parasite and the subsequent response is diverse within the dog population. A spectrum of clinical outcomes exists post-infection where some animals become sub-clinically infected, whereas others develop severe disease with high morbidity and mortality. Development of cell-mediated immunity is essential for control of the parasite burden. The absence of an adequate T cell response, with production of high levels of antibody and/or regulatory cytokines (e.g. IL-10), typically leads to appearance of severe clinical disease. Immune response genes, particularly those encoding the Dog Leukocyte Antigen (DLA) are highly polymorphic. This allows diversity of immune responses within a population, an evolutionary advantage when dealing with mutating pathogens. Selective breeding of dogs has resulted in considerable interbreed but often minimal intra-breed variability in both innate and adaptive immune response genes, which is likely to impact on immune responses to infection and vaccination. Thus, individuals and some breeds may carry alleles that are detrimental in this particular infection. Most vaccine trials are undertaken in Beagle dogs that are somewhat restricted in the DLA alleles they express. This is likely to influence the results of vaccine trials, in which these animals are used. AIMS AND OBJECTIVES The aim of this project is to test the HYPOTHESES that canine immune response genes are associated with susceptibility and resistance to Leishmania infection and that these genes also determine the response to vaccination. Two populations will be studied; the first will consist of dogs recruited from endemic areas, that are exposed to natural infection and whose disease and immunological status have been established, the second will consist of laboratory Beagles that are being used for leishmania vaccine studies by the industrial partner. The hypotheses will be tested by pursuing the following objectives: 1) Single nucleotide polymorphisms (SNPs) have previously been characterised for a variety of canine innate immune response genes (TLRs, TNF-alpha, IL-12beta, IL-18) and adaptive immune response genes (DLA, CTLA4, IFN-gamma, IL-4, IL-10). A case : control association study will be performed using clinically affected cases and asymptomatic infected controls to identify susceptibility / resistance alleles and haplotypes. 2) Beagles will be genotyped for innate and adaptive immune response genes to establish the degree of restriction within this inbred population compared to the general dog population. Breeding pairs will be selected based on maintaining diversity and heterozygosity in litters to be used for vaccine trials. Puppies will be genotyped prior to entry into vaccine trials to ensure matching between vaccinated and control groups. 3) Following completion of vaccine trials, genetic factors associated with immune responses to vaccination will be investigated. This will aim to identify specific loci/genes that are associated with variability in the cell-mediated IFN-gamma response (low to high; increasing resistance) and antibody response (low to high; increasing susceptibility). Quantitative Trait Loci (QTL) mapping will be undertaken, using the Illumina Canine SNP20 BeadChip system to identify loci and associated genes that are associated with variability in immune responses.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

The Centre's themes align with the 'Towards A Data Driven Future' and 'Enabling Intelligence' priority areas, meeting the needs identified by UKRI to provide a highly skilled - and in demand - workforce focused on ensuring positive, human-centred benefits accrued from innovations in data driven and intelligence-based systems. The Centre has a distinct and methodologically challenging "people-first" perspective: unlike an application-orientated approach (where techniques are applied to neatly or simplistically defined problems, sometimes called "solutionism"), this lens will ensure that intense, multi-faceted and iterative explorations of the needs, capabilities and values of people, and wider societal views, challenge and disrupt computational science. In a world of big data and artificial intelligence, the precious smallness of real individuals with their values and aspirations are easily overlooked. Even though the impact of data-driven approaches and intelligence are only beginning to be felt at a human scale, there are already signs of concern over what these will mean for life, with governments and others worldwide addressing implications for education, jobs, safety and indeed even what is unique in being human. Sociologists, economists and policy makers of course have a role in ensuring positive outcomes for people and society of data-driven and intelligence systems; but, computational scientists have a pivotal duty too. Our viewpoint, then, will always see the human as a first-class citizen in the future physical-digital world, not perceiving themselves as outwitted, devalued or marginalised by the expanding capabilities of machine computation, automation and communication. Swansea and the wider region of Wales is a place and community where new understandings of data science and machine intelligence are being formed within four challenging contexts defined in the Internet Coast City Deal: Life Science and Well-being; Smart Manufacturing; Smart and Sustainable Energy; and Economic Acceleration. Studies commissioned by the City Deal and BEIS evidence the science and innovation strengths in Swansea and region in these areas and indicate how transformational investments in these areas will be for the region and the UK. Our Centre will, then, immerse cohorts in these contexts to challenge them methodologically and scientifically. The use of data-driven and intelligence systems in each of the four contexts gives rise to security, privacy and wider ethical, legal, governance and regulatory issues and our Centre also has a cross-cutting theme to train students to understand, accommodate and shape current and future developments in these regards. Cohort members will work to consider how the Centre's challenge themes direct and drive their thinking about data and intelligence, benefitting from both the multidisciplinary team that have built strong research agendas and connections with each of the contexts and the rich set of stakeholders that are our Centre has assembled. Importantly, a process of pivoting between challenge themes will be applied: insights, methods and challenges from one theme and its research projects will be tested and extended in others with the aim of enriching all. These, along with several other mechanisms (such as intra- and inter-cohort sandpits and side projects) are designed to develop a powerful bonding and shaping "cohort effect". The need for and value of our Centre is evidenced by substantial external industrial investment we have have secured: £1,750,000 of cash and £4,136,050 in-kind (total:£5,886,050). These partners and stakeholders have helped create the vision and detail of the proposal and include: Vint Cerf ("father of the internet" and Vice President of Google); NHS; Pfizer; Tata Steel; Ford; QinetiQ; McAfee; Ordnance Survey; Facebook; IBM; Microsoft; Fujitsu; Worshipful Company of IT Spiritual and Ethical Panel; and, Vicki Hanson (CEO, Association of Computing Machinery).